Monday, July 11, 2011

The Magic Johnson Effect Returns

As someone who works with HIV/AIDS patients, especially a good deal of newly diagnosed patients, I've probably been asked about Magic Johnson more times than Larry Bird himself.  The questions usually fall into two basic categories: Has Magic been cured? and Which meds are Magic on because they have to be the best since he's lived so long (or substitute "cured")?  Well as many of us know or should know, there is no cure for HIV and "undetectable", which is defined as a viral load of <20 copies per ml, is often thought to be interchangeable with "cured" by those that are newly diagnosed.  As I often explain, Magic is not on any magic meds and his meds are not right for everybody.  Recently though, I've had to amend this a bit to account for an exciting new case.

Enter the Berlin Patient

I'm not writing a blog entry to retell the story of the Berlin patient.  You can Google it until your heart is content and you'll be able to find out more than enough information to get you up to speed.  However if you're too lazy to do that, here are three other options:

A Basic Description
 http://www.examiner.com/city-buzz-in-san-francisco/the-berlin-patient-first-reports-of-an-aids-cure

Infectious Disease All-Star Clinician
Blood Journal's piece is excellent. http://bloodjournal.hematologylibrary.org/content/117/10/2791.full.pdf

The Quick and Dirty

 -HIV + man with Leukemia receives a stem cell transplant with the kicker being his uber-smart doc, Dr. Gero Huetter,  scored him HIV resistant stem cells aka The Delta Deletion!

-HIV uses two basic "doorways" or co-receptors to enter a CD4 cell.  The main door if you will is CCR5.  The side door or less popular one is CXCR4.

-The Delta Deletion refers to CCR5-delta 32.  These lucky individuals are naturally somewhat resistant to HIV because their CD4 cells don't have the CCR5 receptors.  The fly in the ointment is that different strands of HIV can use different doors.  Dual tropism refers to a virus that can either the CCR5 or the CXCR4.  This is where the "somewhat" comes in as someone with the delta deletion is ABSOLUTELY NOT resistant to HIV that can use CXCR4.

-The Delta Deletion is not absolute as in if you inherit it from one parent you might only have a lower amount of CCR5 receptors.  The Berlin patient was lucky enough to score a donor with two parents with the deletion.

-The patient remained on HAART until the day of his transplant

-Next Dr. Huetter and the team, as is SOP with Leukemia, destroyed his immune system/"conditioned" him and gave the usual regimen of drugs to prevent GVHD

-This would not only kill off most of the Leukemia but the cells infected with HIV as well. 

-They repopulated his immune system with the Delta Deletion donor cells which should make short work of the Leukemia.

-The biggest barrier to curing HIV is getting the viral reservoirs to empty or purge their stash. If we could get them to do that, then it's easy enough to kill it.

-With the barrier to the cure in mind; it's HYPOTHESIZED that the viral reservoirs started emptying out.  They then began hunting for susceptible cells and killed what few were available BUT...once those were gone, they now had no where to go because the new cells aka the Delta Deletion cells, were immune. The virus is simply SOL at this point and dies off.  There are a few holes in this theory though and I'll discuss them in the Burning Questions section.

-Post-transplants-he had two because of a leukemia relapse- he has remained HIV free both at the plasma and tissue levels.

-Short of a brain biopsy (totally inaccessible and believed to be a virus super hide-out), he has been HIV free for ~3.5 years.

My Burning Questions

-As alluded to earlier, he is still susceptible to CXCR4 virus so why didn't the viral reservoir stowaways just use the side door and take over the new cells?  What's that you say-The Delta Deletion down regulates CXCR4 expression?  I'm way ahead of ya blood!  According to Blood, as in Blood Journal, as in the issue I cited above, " in the patient described here, we found no evidence for an abnormal CXCR4 expression on recovered CD4 T Cells 

ADDENDUM 10-6-11: After speaking with a pharmacist and reviewing the Blood Journal article it was brought to my attention that the pt was not dual tropic.  Using deep sequencing techniques it was determined that he does have CXCR4 variants but he does not have a dual tropic virus.  Some concerns are that eventually these variants will surface and he will be "re-infected" but from what I understand there is a big difference between using deep sequencing techniques to detect variants and a true dual tropic virus.

-Paging Maraviroc! Paging Maraviroc! Am I the only one that knows about the CCR5 antagonist currently in use?  Have I sipped too many coffees and Diet Mountain Dews and succumbed to the mysterious but never articulately described poisons of caffeine that the judging eyes always warn me about? Maraviroc already blocks the CCR5 receptors in patients who have a virus that only uses the front door.  In fact, one of the big issues with Maraviroc was/is when to use it.  You see, pts are more likely to have dual tropism viruses as the dz progresses, at which point Maraviroc is useless and until a more sensitive assay came out, it was not approved for HAART naive pts.  This brings us back to the beginning! So if Maraviroc is useless in dual tropism pts, then why did replacing the Berlin pt's immune system with a CCR5 free version work because he was 100%, absolutely confirmed, CXCR4 capable

ADDENDUM 10-6-11: Again see above.  Several blogs and nonprofessional sources have listed him as dual tropic but he just had CXCR4 variants using deep sequencing techniques.  This is NOT the same as a dual tropism.

-While everyone is very impressed with this "cure", the Debby-downers, myself included, are quick to point out that giving the ~33 million HIV+ patients in the world, chemo and stem cell transplants isn't feasible....BUT is it?

-Let's just assume that this medical miracle was as sure as death and taxes and would cure anybody infected.  What are the real barriers?

-How about a lack of donors: <2% of Western Europeans have the Delta Deletion.  Northern Europeans carry the highest prevalence with a whopping 4%.  For you trivia buffs, this is believed to have originated as an evolutionary response to the Plague.

-Going through chemo and a transplant is akin to walking into the bar and copping a feel on Mrs. Death's fanny, spitting in Death's drink, and then headbutting him. Make no mistake my friend, there will be consequences and to think you can just run everybody through "conditioning" and a transplant like some ride at Six Flags is infantile.

-Let's assume you win the bar fight against the Reaper.  How about cost? I have an MBA and tend to think of everything in dollars which tends to make opinions about me very divisive.  The dollar literally makes the world go around and for those of you that have had an Econ class you know I'm right. Assuming it would work and everyone would survive, is it cost effective?

-There are numerous things to nitpick about these figures but I tried to be as conservative as possible and while they may not be precise, I don't think you can argue with the overall message.

-The average life expectancy for a 19 y/o diagnosed with HIV is ~40 years.  Treatment cost estimates range from $14,000 to $20,000 per year according to http://www.everydayhealth.com/hiv-aids/can-you-afford-hiv-treatment.aspx.  Let's be conservative and go high for a total of $800k for the lifetime. According to http://www.businessweek.com/magazine/content/05_36/b3949007_mz001.htm a transplant runs about $260K and according to http://www.everydayhealth.com/leukemia/the-high-cost-of-leukemia-treatment.aspx they could run as high as $500k.  One round of chemo runs $150k according to http://www.benzene-illness.com/html/medical-expenses.html.  The Berlin patient had at least two rounds of chemo and two transplants but let's run some scenarios shall we..

-One round of chemo and one transplant: $150K + $260K = $410K  $410K<$800K.  Assuming there are no other costs, which is likely assuming ENTIRELY too much, this is cost-effective.

-One round of chemo and one expensive-er transplant: $150K + $500K = $650 K.
$650K < $800K  Assuming there are no other costs, which is likely assuming ENTIRELY too much, this is cost-effective.

-Two rounds of chemo and two transplants: $300K + $520K = $820K. $820K>$800K so this IS NOT cost effective and I'm sure you can do the math from here.  However...are you going to let them go through one, have it not work and then pull the plug on the project? Unless your name ends in "bub" that's pretty harsh.

-To play Devil's/bub's advocate: there are about 33 million people with HIV in the world that we know of.  $33M x an average cost of $400K per lifetime (the conservative trend continues!) $13,200,000,000,000.

-According to  http://www.avert.org/aids-funding.htm we spent $15.6 Billion in 2008.  Divide $15.6 Billion by $33 Million and it comes out to $472.73.  Remember, on the low end, we were saying it costs about $14K/year to treat.  Even without everybody on HAART, you can see we can't and DON'T afford this epidemic.  Have you come down with compassion fatigue?  Well read that twice and call me in the morning.

Summary

-Short of a brain biopsy, YES, they have cured HIV but it's about as functional as touting winning the lottery as a cure for poverty

-While the advancements in HAART have largely neutered HIV from it's death dealing ways, not everyone can afford the meds.  In fact almost no one can, hence the disability route and the ever-crippling financial co morbidity of the epidemic.  Furthermore, just by looking at the math you can see that we as a civilization can't afford this epidemic and we don't.

2 comments:

  1. Very interesting and informative post and analysis Josh. We also get a lot of questions about mosquito bites and double condoms.

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  2. I've made some addendums regarding my concerns with his therapy and the fact that I thought he had a dual tropism virus. He does NOT have a dual tropic virus and so my concerns are accounted for.

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